Table 1.
Summary of the included studies.
| Study [Reference] | Study Design (In Vivo) | Study Design (In Vitro) | Findings |
|---|---|---|---|
| Ambrus et al., 1991 [26] | Human malignant melanoma implants in rabbit cornea and non-human primates. | Pentoxifylline inhibited human tumor implant-induced angiogenesis. | |
| Ambrus et al., 1992 [27] | Human malignant melanoma implants in rabbit cornea and non-human primates. | Pentoxifylline inhibited human tumor implant-induced angiogenesis. | |
| Ching et al., 1998 [29] | Interaction of thalidomide, phthalimide analogs of thalidomide and pentoxifylline with anti-tumor agent DMXAA in mice models given Colon 38 tumors. | Pentoxifylline potentiates DMXAA inhibition of serum TNF production. | |
| Joseph & Isaacs, 1998 [44] | Transplanted Dunning R-3327 MAT-Lu rat prostate cancers. Pentoxifylline effects were assessed on tumor-associated macrophages and blood vessel densities. | On human and mouse macrophages. | Pentoxifylline inhibition of macrophage secretion tumor necrosis factor-α and granulocyte–macrophage colony-stimulating factor, and reduction of tumor blood vessel density and tumor growth. |
| Ambrus et al., 2000 [28] | Human malignant melanoma implants in Macaca arctoides monkey cornea. | Pentoxifylline inhibited human tumor implant-induced angiogenesis. | |
| Gude et al., 2001 [45] | C57BL/6J mice model injected with B16-F10 melanoma cells. IC50 7 mM after 24 h exposure. | Growth inhibition of 2 endothelial cell lines. | Significant inhibition of tumor-induced angiogenesis in C57B1/6 mice inoculated with pentoxifylline that paralleled decreased tumor volumes. In vitro pentoxifylline exhibited a dose-response inhibition of endothelial cell growth and downregulation of urokinase-type plasminogen activator expression. |
| Zhang et al., 2009 [30] | Hepatopulmonary syndrome induced in a rat model; pulmonary angiogenesis was assessed by quantifying factor VIII-positive micro vessels and levels of von Willebrand factor, vascular endothelial cadherin, angiogenic factors, and proliferating cell nuclear antigen. | Pentoxifylline-treated rats had a reduction in micro vessels and lung monocyte accumulation, downregulation of pulmonary angiogenic factors, and decreased symptoms of hepatopulmonary syndrome. The authors conclude that pentoxifylline decreases hepatopulmonary syndrome-associated angiogenesis, decreases the associated symptoms, and downregulates VEGF-A mediated pathways. | |
| Mendes et al., 2009 [31] | Murine model of sponge-induced peritoneal adhesion, treated with pentoxifylline and assessed by measuring hemoglobin content, VEGF, and morphometric analysis. | Following treatments of pentoxifylline, hemoglobin content, morphometric, morphometric analysis of vessel number, and levels of VEGF decreased. The results align with previous evidence that anti-VEGF activity is associated with angiogenesis inhibition. | |
| Vlahos et al., 2010 [32] | Surgical induction of endometriosis in rats. Morphological changes and VEGF-C and FLK-1 expression were assessed. | There was a significant reduction in the mean volume of endometriotic implants in the pentoxifylline treatment groups. There was a significant reduction in VEGF-C and FLK-1 expressions. The authors conclude that pentoxifylline may suppress angiogenesis by downregulating VEGF-C and FLK-1 expression. | |
| Boztosun et al., 2012 [33] | Surgical induction of adhesions in rats. Morphological changes and VEGF, bFGF, TGF-β, and PDGF expression were assessed. | Pentoxifylline did not show any effect on the expression of angiogenic factors. | |
| Pratibha et al., 2013 [34] | This study investigated the mechanisms for the antiangiogenic activity of pentoxifylline by injecting B16-F10 melanoma cells into C57BL/6 mice and assessing blood vessel density and molecular markers. IC50 39.2 +/− 1.3 mM after 2 h exposure. | The results of this study demonstrated that pentoxifylline: suppressed STAT3 phosphorylation and its upstage kinases, reduced expression of HIF1α, VEGF, VEGFR1, VEGFR2, and pro-inflammatory cytokines, and suppressed tumor volume and micro vessel density. The authors conclude that pentoxifylline may exert anti-tumor activity by inhibiting angiogenesis through the STAT3 pathway in B16F10 melanoma. | |
| Kamran & Gude, 2013 [46] | Intra-dermal mouse xenograft model was used to assess tumor volume and angiogenesis. IC50 7 mM after 2 h exposure with pentoxifylline. | A375 human melanoma cell line was treated with pentoxifylline and assessed for STAT3 signaling. | Following treatment of the mice with pentoxifylline, there was a significant decrease in the mean volume of the tumors and a reduction in tumor-induced angiogenesis. Pentoxifylline’s tumor growth and angiogenesis inhibition may involve the STAT3 signaling pathways. |
| Nidhyanandan et al., 2015 [47] | MS-275 and pentoxifylline were assessed in a murine Matrigel plug angiogenesis model and human breast cancer (MDA-MB-231) xenograft model. | A panel of cancer cell lines was treated with pentoxifylline and MS-275 and evaluated for cellular proliferation, cell cycle regulation, apoptosis, and anti-angiogenesis. | A combination of MS-275 and pentoxifylline significantly inhibited angiogenesis in the Matrigel plug angiogenesis assay. The combination therapy inhibited the expression of VEGF in a dose-dependent manner. |
| Çakmak et al., 2015 [35] | Sprague–Dawley rats were utilized to determine the effect of pentoxifylline on angiogenesis and bone healing. Radiographic, immunohistochemical methods and histological methods were utilized to evaluate the effect. | Pentoxifylline may improve angiogenesis and healing of segmental cortical bone defects of the radius in a rat model. | |
| Nathan et al., 2016 [36] | Various concentrations of pentoxifylline were tested at 50% epiboly stage (5.2 HPF) of zebrafish embryos and evaluated phenotypic changes and expression of adenosine receptors, HIF-1α, VEGFaa, VEGFr2, and RP-1a. | RBC staining demonstrated an absence of intersegmental vessels in embryos treated with pentoxifylline. Pentoxifylline-treated embryos developed abnormal vasculature. Additional results show inhibition of VEGFAA and adenosine receptions and new blood vessel formation following treatment with pentoxifylline. | |
| Bałan et al., 2017 [37] | Tumor cells were incubated with various concentrations of pentoxifylline before transplantation into mice. | The results of this study demonstrate that pentoxifylline had an inhibitory effect on tumor growth and volume and had a dose-dependent decrease in angiogenesis following transplantation. | |
| Niderla-Bielińska et al., 2018 [41] | Mouse embryo proepicardium was harvested and treated with pentoxifylline to assess the expression of angiogenic factors. Endothelial cell line C166 was derived from embryonic yolk sac treated with pentoxifylline to assess the direct effect on angiogenesis. | Pentoxifylline indirectly inhibits angiogenesis in mouse proepicardial explant cultures by decreasing Dll4 and Notch1 expression but has no significant effect on the C166 endothelial cell line. | |
| Yang et al., 2018 [38] | A mouse model was used to investigate pentoxifylline’s effect on postoperative intra-abdominal adhesion formation through angiogenesis and other physiological processes. Angiogenesis was assessed via immunohistology analysis of angiogenesis markers Ki67+/CD31+. | Pentoxifylline significantly suppressed angiogenesis during the peritoneal repair of the mice. The authors state that these findings are in line with additional studies on the inhibition of angiogenesis. | |
| Arsenyan et al., 2020 [42] | Matrigel (BD Biosciences) human umbilical vein endothelial cell tube formation model was used to investigate various compounds’ angiogenesis and MMP inhibition activity. | The study results show that pentoxifylline did not inhibit any of the studied matrix metalloproteinases. The authors presume that the lack of correlations between MMP and angiogenesis inhibition indicates that the compounds modulate angiogenesis via different mechanisms. | |
| Pedretti et al., 2020 [39] | Rat model of skin flap surgical procedure, then treated with subcutaneous pentoxifylline. VEGF and TGF-β1 levels were measured. | Pentoxifylline stimulated angiogenesis and reepithelization while reducing fibrogenesis. | |
| Seo et al., 2020 [40] | Rat model of radiation-induced osteoradionecrosis. Treated with pentoxifylline alone and with pentoxifylline and tocopherol. Angiogenesis effects were assessed. | Pentoxifylline and tocopherol work synergistically to promote angiogenesis, while pentoxifylline alone had a slight increase in proangiogenic factors PECAM, VEGF-A, and TNF-α. | |
| Seo et al., 2021 [43] | The effects of pentoxifylline on RAW 264.7 cells were analyzed with immunoprecipitation high-performance liquid chromatography to assess angiogenesis inhibition via the expression levels of VEGF-A, vWF, ET-1, CD31, MMP-10, and VCAM. | The expression levels of VEGF-A, vWF, ET-1, CD31, MMP-10, and VCAM showed a minimal change within 5%. The results of this study show that pentoxifylline has a weak angiogenic effect over 48 h. |
Abbreviations: C57BL/6J: C57 black 6J; CD31: Cluster of differentiation 31; C166: Cellosaurus 166; Dll4: Delta-like 4; DMXAA: 5,6-dimethylxanthenone-4-acetic acid; ET-1: Endothelin 1; FGF: Fibroblast growth factor; Flk-1: Fetal Liver Kinase-1; MDA-MB-231: M.D. Anderson—Metastatic Breast 231; MMP: matrix metalloproteinase; MS-275: Entinostat; Notch1: Neurogenic locus notch homolog protein 1; NRP-1a: neuropilin 1a; PECAM: Platelet endothelial cell adhesion molecule, PDGF: Platelet-derived growth factor; RAW 264.7: Ralph Raschke Watson cell line 264.7; R-3327 MAT-Lu: R-3327 metastatic, anaplastic tumor to the lung; STAT3: Signal transducer and activator of transcription 3; TGF: tumor growth factor; TNF: tumor necrosis factor; VCAM: vascular cell adhesion molecule; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; vWF: von Willibrand factor.